Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endothelial cells forming aberrant lumens similar to those seen in vascular malformations. ATAC-seq analysis reveals activation of c-Kit in the novel vascular malformations. We demonstrate that c-Kit is expressed in authentic human Sturge–Weber vascular malformations, indicating a novel druggable target for Sturge–Weber syndrome. Since c-Kit is targeted by the FDA-approved drug imatinib, we tested the ability of imatinib on the phenotype of the vascular malformations in vivo. Imatinib treated vascular malformations are significantly smaller and have decreased supporting stromal cells surrounding the lumen. Imatinib may be useful in the treatment of human vascular malformations that express c-Kit, including Sturge–Weber syndrome.

Study Designs for Evaluation of Combination Treatment: Focus On Individual Patient Benefit

Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We here review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level over-estimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).